EP0816837A1 - Variable control of electroosmotic and/or electrophoretic forces within a fluid-containing structure via electrical forces - Google Patents

Abstract

In a microfluidic system using electrokineticforces, the present invention uses electrical current orelectrical parameters, other than voltage, to control themovement of fluids through the channels of the system. Time-multiplexedpower supplies also provide further control overfluid movement by varying the voltage on an electrodeconnected to a fluid reservoir of the microfluidic system, byvarying the duty cycle during which the voltage is applied tothe electrode, or by a combination of both. A time-multiplexedpower supply can also be connected to more thanone electrode for a savings in cost.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S.Patent Application Serial No. 08/678,436, filed July 3, 1996,which is incorporated herein by reference in its entirety forall purposes.

BACKGROUND OF THE INVENTION

There has been a growing interest in the manufactureand use of microfluidic systems for the acquisition ofchemical and biochemical information. Techniques commonlyassociated with the semiconductor electronics industry, suchas photolithography, wet chemical etching, etc., are beingused in the fabrication of these microfluidic systems. Theterm, "microfluidic", refers to a system or device havingchannels and chambers which are generally fabricated at themicron or submicron scale, e.g., having at least one cross-sectionaldimension in the range of from about 0.1 µm to about500 µm. Early discussions of the use of planar chiptechnology for the fabrication of microfluidic systems areprovided in Manz et al.,Trends in Anal. Chem. (1990)10(5):144-149 and Manz et al.,Avd. in Chromatog. (1993) 33:1-66,which describe the fabrication of such fluidic devices andparticularly microcapillary devices, in silicon and glasssubstrates.

Applications of microfluidic systems are myriad.For example, International Patent Appln. wO 96/04547,published February 15, 1996, describes the use of microfluidicsystems for capillary electrophoresis, liquid chromotography,flow injection analysis, and chemical reaction and synthesis.A related patent application, U.S. Appln. No.    , entitled"HIGH THROUGHPUT SCREENING ASSAY SYSTEMS IN MICROSCALE FLUIDICDEVICES", filed June 28, 1996 by J. Wallace Parce et al. and assigned to the present assignee, discloses wide rangingapplications of microfluidic systems in rapidly assayingcompounds for their effects on various chemical, andpreferably, biochemical systems. The phrase, "biochemicalsystem" generally refers to a chemical interaction thatinvolves molecules of the type generally found within livingorganisms. Such interactions include the full range ofcatabolic and anabolic reactions which occur in living systemsincluding enzymatic, binding, signaling and other reactions.Biochemical systems of particular interest include, e.g.,receptor-ligand interactions, enzyme-substrate interactions,cellular signaling pathways, transport reactions involvingmodel barrier systems (e.g., cells or membrane fractions) forbioavailability screening, and a variety of other generalsystems.

Many methods have been described for the transportand direction of fluids, e.g., samples, analytes, buffers andreagents, within these microfluidic systems or devices. Onemethod moves fluids within microfabricated devices bymechanical micropumps and valves within the device. See,Published U.K. Patent Application No. 2 248 891 (10/18/90),Published European Patent Application No. 568 902 (5/2/92),U.S. Patent Nos. 5,271,724 (8/21/91) and 5.277,556 (7/3/91).See also, U.S. Patent No. 5,171,132 (12/21/90) to Miyazaki etal. Another method uses acoustic energy to move fluid sampleswithin devices by the effects of acoustic streaming. See,Published PCT Application No. 94/05414 to Northrup and White.A straightforward method applies external pressure to movefluids within the device. See, e.g., the discussion in U.S.Patent No. 5,304,487 to Wilding et al.

Still another method uses electric fields, and theresulting electrokinetic forces, to move fluid materialsthrough the channels of the microfluidic system. See, e.g.,Published European Patent Application No. 376 611 (12/30/88)to Kovacs, Harrison et al.,Anal. Chem. (1992) 64:1926-1932and Manz et al.J. Chromatog. (1992) 593:253-258, U.S. PatentNo. 5,126,022 to Soane. Electrokinetic forces have theadvantages of direct control, fast response and simplicity. However, there are still some disadvantages with this methodof operating a microfluidic system.

Present devices use a network of channels in asubstrate of electrically insulating material. The channelsconnect a number of fluid reservoirs in contact with highvoltage electrodes. To move fluid materials through thenetwork of channels, specific voltages are simultaneouslyapplied to the various electrodes. The determination of thevoltage values for each electrode in a system becomes complexas one attempts to control the material flow in one channelwithout affecting the flow in another channel. For example,in a relatively simple arrangement of four channelsintersecting in a cross with reservoirs and electrodes at theends of the channels, an independent increase of fluid flowbetween two reservoirs is not merely a matter of increasingthe voltage differences at the two reservoirs. The voltagesat the other two reservoirs must also be adjusted if theiroriginal flow and direction are to be maintained.Furthermore, as the number of channels, intersections, andreservoirs are increased, the control of fluid through thechannels become more and more complex.

Also, the voltages applied to the electrodes in thedevice can be high, i.e., up to a level supportive ofthousands of volts/cm. Regulated high voltage supplies areexpensive, bulky and are often imprecise and a high voltagesupply is required for each electrode. Thus the cost of amicrofluidic system of any complexity may become prohibitive.

The present invention solves or substantiallymitigates these problems of electrokinetic transport in amicrofluidic system which uses another electrical parameter,rather than voltage, to simplify the control of material flowthrough the channels of the system. A high throughputmicrofluidic system having direct, fast and straightforwardcontrol over the movement of materials through the channels ofthe microfluidic system with a wide range of applications,such as in the fields of chemistry, biochemistry,biotechnology and molecular biology and numerous other fields,is possible.

SUMMARY OF THE INVENTION

The present invention provides for a microfluidicsystem with a plurality of interconnected capillary channelsand a plurality of electrodes at different nodes of thecapillary channels which create electric fields in thecapillary channels to electrokinetically move materials in afluid through the capillary channels. In accordance with thepresent invention, the microfluidic system is operated byapplying a voltage between a first electrode and a secondelectrode responsive to an electrical current between thefirst and second electrodes to move materials therebetween.Electrical current can give a direct measure of ionic flowthrough the channels of the microfluidic system. Besidescurrent, other electrical parameters, such as power, may bealso used.

Furthermore, the present invention provides fortime-multiplexing the power supply voltages on the electrodesof the microfluidic system for more precise and efficientcontrol. The voltage to an electrode can be controlled byvarying the duty cycle of the connection of the electrode tothe power supply, varying the voltage to the electrode duringthe duty cycle, or a combination of both. In this manner, onepower supply can service more than one electrode.

The present invention also provides for the directmonitoring of the voltages within the channels in themicrofluidic system. Conducting leads on the surface of themicrofluidic system have widths sufficiently narrow in achannel to prevent electrolysis. The leads are connected tovoltage divider circuits also on the surface of the substrate.The divider circuit lowers the read-out voltage of the channelnode so that special high-voltage voltmeters are not required.The divider circuits are also designed to draw negligiblecurrents from the channels thereby minimizing unwantedelectrochemical effects, e.g., gas generation, reduction/oxidation reactions.

The invention as hereinbefore described may be putto a plurality of different uses, which are themselvesinventive, for example, as follows:

The use of a substrate having at least one channelin which a subject material is transportedelectrokinetically, by applying a voltage between twoelectrodes associated with the channel in response to acurrent at the electrodes.

A use of the aforementioned invention, in which thesubstrate has a plurality of interconnected channels andassociated electrodes, subject material being transportedalong predetermined paths incorporating one or more ofthe channels by the application of voltages topredetermined electrodes in response to a current at theelectrodes.

The use of a substrate having at least one channelin which a subject material is transportedelectrokinetically by the controlled time dependentapplication of an electrical parameter between electrodesassociated with the channel.

A use of the aforementioned invention, wherein theelectrical parameter comprises voltage, current or power.

The use of an insulating substrate having aplurality of channels and a plurality of electrodesassociated with the channels, the application of voltagesto the electrodes causing electric fields in thechannels, and at least one conductive lead on thesubstrate extending to a channel location so that anelectric parameter at the channel location can bedetermined.

A use of the aforementioned invention, wherein theconductive lead has a sufficiently small width such thata voltage of less than 1 volt, and preferably less than0.1 volt, is created across the conductive lead at thechannel location.

A use of an insulating substrate having a pluralityof interconnected capillary channels, a plurality ofelectrodes at different nodes of the capillary channels for creating electric fields in the capillary channels tomove materials electrokinetically in a fluid through thecapillary channels, a power supply connected to at leastone of the electrodes, the power supply having a mixingblock having a first input terminal for receiving acontrollable reference voltage and a second inputterminal, and an output terminal; a voltage amplifierconnected to the mixing block output terminal, thevoltage amplifier having first and second outputterminals, the first output terminal connected to the atleast one electrode; and a feedback block connected tothe first output terminal of the voltage amplifier, thefeedback block having an output terminal connected to thesecond input terminal of the mixing block so thatnegative feedback is provided to stabilize the powersupply.

The use of the aforementioned invention, in whichthe feedback block is also connected to the second outputterminal of the voltage amplifier, the feedback blockgenerating a first feedback voltage responsive to avoltage at the first output terminal and a secondfeedback voltage responsive to an amount of current beingdelivered to the at least one electrode through the firstoutput terminal, the feedback block having a switch forpassing the first or second feedback voltage to themixing block responsive to a control signal so that thepower supply is selectably stabilized by voltage orcurrent feedback.

The use of a power supply for connection to at leastone electrode of a microfluidic system in which the powersupply has a mixing block having a first input terminalfor receiving a controllable reference voltage and asecond input terminal, and an output terminal; a voltageamplifier connected to the mixing block output terminal,the voltage amplifier having first and second outputterminals, the first output terminal connected to the atleast one electrode; and a feedback block connected tothe first and second output terminals of the voltage amplifier and to the second input terminal of the mixingblock, the feedback block generating a first feedbackvoltage responsive to a voltage at the first outputterminal and a second feedback voltage responsive to anamount of current being delivered to the at least oneelectrode through the first output terminal, the feedbackblock having a switch for passing the first or secondfeedback voltage to the mixing block responsive to acontrol signal so that the power supply is selectablystabilized in voltage or current by negative feedback.

The use of a microfluidic system in which asubstrate has a plurality of interconnected capillarychannels, a plurality of electrodes at different nodes ofthe capillary channels for creating electric fields inthe capillary channels to move materialselectrokinetically in a fluid through the capillarychannels, and a plurality of power supplies connected toeach one of the electrodes, each of the power suppliescapable of selectively supplying a selected voltage and aselected amount of current as a source or sink to theconnected electrodes.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows a representative illustration of amicrofluidic system;

Figure 2A illustrates an exemplary channel of amicrofluidic system, such as that of Figure 1; Figure 2Brepresents the electrical circuit created along the channel inFigure 2A;

Figure 3A is a graph of output voltage versus timefor a prior art power supply; Figure 3B is a graph of outputvoltage versus time for a time-multiplexed power supplyaccording to the present invention;

Figure 4A is a representative illustration of amicrofluidic system operating with time-multiplexed voltagesaccording to the present invention; Figure 4B is a blockdiagram illustrating the units of a power supply in Figure 4A;

Figure 5A is a representative illustration of amicrofluidic system with voltage-monitored nodes according tothe present invention; Figure 5B details the voltage dividercircuit of Figure 5A; and

Figure 6A is a block diagram of the power supplyunit of Figure 4B; Figure 6B is an amplifier blockrepresentation of the DC-DC converter block of Figure 6A.

DETAILED DESCRIPTION OF THE INVENTION

Figure 1 discloses a representative diagram of aportion of an exemplarymicrofluidic system 100 operatingaccording to the present invention. As shown, theoverallsystem 100 is fabricated in aplanar substrate 102. Suitablesubstrate materials are generally selected based upon theircompatibility with the conditions present in the particularoperation to be performed by the device. Such conditions caninclude extremes of pH, temperature, ionic concentration, andapplication of electrical fields. Additionally, substratematerials are also selected for their inertness to criticalcomponents of an analysis or synthesis to be carried out bythe system.

The system shown in Figure 1 includes a series ofchannels 110, 112, 114 and 116 fabricated into the surface ofthesubstrate 102. As discussed in the definition of"microfluidic," these channels typically have very small crosssectional dimensions. For the particular applicationsdiscussed below, channels with depths of about 10 µm andwidths of about 60 µm work effectively, though deviations fromthese dimensions are also possible. Themicrofluidic system100 transports subject materials through the various channelsof thesubstrate 102 for various purposes, including analysis,testing, mixing with other materials, assaying andcombinations of these operations. The term, "subjectmaterials," simply refers to the material, such as a chemicalor biological compound, of interest. Subject compounds mayinclude a wide variety of different compounds, includingchemical compounds, mixtures of chemical compounds, e.g.,polysaccharides, small organic or inorganic molecules, biological macromolecules, e.g., peptides, proteins, nucleicacids, or extracts made from biological materials, such asbacteria, plants, fungi, or animal cells or tissues, naturallyoccurring or synthetic compositions.

Useful substrate materials include, e.g., glass,quartz, ceramics and silicon, as well as polymeric substrates,e.g., plastics. In the case of conductive or semiconductivesubstrates, there should be an insulating layer on thesubstrate. This is important since the system useselectroosmotic forces to move materials about the system, asdiscussed below. In the case of polymeric substrates, thesubstrate materials may be rigid, semi-rigid, or non-rigid,opaque, semi-opaque or transparent, depending upon the use forwhich they are intended. For example, systems which includean optical or visual detection element, are generally befabricated, at least in part, from transparent materials toallow, or at least, facilitate that detection. Alternatively,transparent windows of glass or quartz, e.g., may beincorporated into the device for these types detectionelements. Additionally, the polymeric materials may havelinear or branched backbones, and may be crosslinked or non-crosslinked.Examples of particularly preferred polymericmaterials include, e.g., polydimethylsiloxanes (PDMS),polyurethane, polyvinylchloride (PVC) polystyrene,polysulfone, polycarbonate, polymethylmethacrylate (PMMA) andthe like.

Manufacturing of these channels and other microscaleelements into the surface of thesubstrate 102 may be carriedout by any number of microfabrication techniques that are wellknown in the art. For example, lithographic techniques may beemployed in fabricating glass, quartz or silicon substrates,for example, with methods well known in the semiconductormanufacturing industries. Photolithographic masking, plasmaor wet etching and other semiconductor processing technologiesdefine microscale elements in and on substrate surfaces.Alternatively, micromachining methods, such as laser drilling,micromilling and the like, may be employed. Similarly, forpolymeric substrates, well known manufacturing techniques may also be used. These techniques include injection moldingtechniques or stamp molding methods where large numbers ofsubstrates may be produced using, e.g., rolling stamps toproduce large sheets of microscale substrates or polymermicrocasting techniques wherein the substrate is polymerizedwithin a micromachined mold.

Besides thesubstrate 102, themicrofluidic system100 includes an additional planar element (not shown) whichoverlays the channeledsubstrate 102 to enclose and fluidlyseal the various channels to form conduits. The planar coverelement may be attached to the substrate by a variety ofmeans, including, e.g., thermal bonding, adhesives or, in thecase of certain substrates, e.g., glass, or semi-rigid andnon-rigid polymeric substrates, a natural adhesion between thetwo components. The planar cover element may additionally beprovided with access ports and/or reservoirs for introducingthe various fluid elements needed for a particular screen.

Thesystem 100 shown in Figure 1 also includesreservoirs 104, 106 and 108, which are disposed and fluidlyconnected at the ends of thechannels 114, 116 and 110respectively. As shown, the channel 112 is used to introducea plurality of different subject materials into the device.As such, the channel 112 is fluidly connected to a source oflarge numbers of separate subject materials which areindividually introduced into the channel 112 and subsequentlyinto anotherchannel 110 for electrophoretic analysis, forexample. The subject materials are transported influid slugregions 120 of predetermined ionic concentrations. Theregions are separated by buffer regions of varying ionicconcentrations and represented bybuffer regions 121 inFigure 1. Related patent applications, U.S. Appln. No.08/671,986, filed June 28, 1996, and U.S. Appln. No.08/760,446, filed December 6, 1996, both entitled"ELECTROPIPETTOR AND COMPENSATION MEANS FOR ELECTROPHORETICBIAS," by J. Wallace Parce and Michael R. Knapp, and assignedto the present assignee, explain various arrangements ofslugs, and buffer regions of high and low ionic concentrationsin transporting subject materials with electrokinetic forces. The applications are incorporated herein by reference in theirentirety for all purposes.

To move materials through thechannels 110, 112, 114and 116, a voltage controller which is capable ofsimultaneously applying selectable voltage levels, includingground, to each of the reservoirs, may be used. Such avoltage controller may be implemented using multiple voltagedividers and relays to obtain the selectable voltage levels.Alternatively, multiple independent voltage sources may beused. The voltage controller is electrically connected toeach of the reservoirs via an electrode positioned orfabricated within each of thereservoirs 104, 106 and 108.See, for example, published International Patent ApplicationNo. WO 96/04547 to Ramsey, which is incorporated herein byreference in its entirety for all purposes.

Besides complexity, there are other problems withvoltage control in a microfluidic system. Figure 2Aillustrates anexemplary channel 130 between tworeservoirs132 and 134, each respectively in contact withelectrodes 133and 135, connected to electrical leads are shown leading offthesubstrate 128. To make the example more realistic, thechannel 130 is shown as being connected to twoother channels136 and 138. Operationally, thereservoir 132 is a source forslugs 120 containing the subject material. Theslugs 120 aremoved toward thereservoir 134, which acts as a sink. Thechannels 136 and 138 providebuffer regions 121 to separatetheslugs 120 in thechannel 130.

The different resistances of theslugs 120 andbuffer regions 121 in thechannel 130 create an electricalcircuit which is symbolically indicated in this simpleexample. The voltage V applied between the twoelectrodes 133and 135 is:

where I is the current between the twoelectrodes 133, 135(assuming no current flow into 136, 138) and R_i the resistanceof thedifferent slugs 120 andbuffer regions 121.

A voltage control system is subject to many factorswhich can interfere with the operation of the system. Forexample, the contact at the interface between an electrode andfluid may be a source of problems. When the effectiveresistance of the electrode-to-fluid contact varies due tocontaminants, bubbles, oxidation, for example, the voltageapplied to the fluid varies. With V set at the electrodes, adecrease in electrode surface area contacting the solution dueto bubble formation on the electrode causes an increase inresistance from the electrode to the solution. This reducesthe current between electrodes, which in turn reduces theinduced electroosmotic and electrophoretic forces in thechannel 130.

Other problems may affect the channel current flow.Undesirable particulates may affect the channel resistance byeffectively modifying the cross-sectional area of the channel.Again, with a change of channel resistance, the physicalcurrent flow is changed.

With other channels, such aschannels 136 and 138,connected to theexemplary channel 130, dimensional variationsin the geometry of the channels in thesubstrate 102 canseriously affect the operation of a voltage control system.For example, the intersection node for thechannels 130, 136and 138 might be X distance from the electrode for thereservoir at the terminus of the channel 136 (not shown)and Ydistance from the electrode for the reservoir at the terminusof the channel 138 (not shown). With a slight lateralmisalignment in the photolithographic process, the distances Xand Y are no longer the same for the microfluidic system onanother substrate. The voltage control must be recalibratedfrom substrate to substrate, a time-consuming and expensiveprocess, so that the fluid movement at the intersection nodecan be properly controlled.

To avoid these problems, the present invention useselectric current control in themicrofluidic system 100. Theelectrical current flow at a given electrode is directlyrelated to the ionic flow along the channel(s) connecting thereservoir in which the electrode is placed. This is in contrast to the requirement of determining voltages at variousnodes along the channel in a voltage control system. Thus thevoltages at the electrodes of themicrofluidic system 100 areset responsive to the electric currents flowing through thevarious electrodes of thesystem 100. Current control is lesssusceptible to dimensional variations in the process ofcreating the microfluidic system on thesubstrate 102.Current control permits far easier operations for pumping,valving, dispensing, mixing and concentrating subjectmaterials and buffer fluids in a complex microfluidic system.Current control is also preferred for moderating undesiredtemperature effects within the channels.

Of course, besides electric current which provides adirect measure of ionic flow between electrodes, otherelectrical parameters related to current, such as power, maybe used as a control for themicrofluidic system 100. Powergives an indirect measurement of the electric current throughan electrode. Hence the physical current between electrodes(and the ionic flow) can be monitored by the power through theelectrodes.

Even with a current control system described above,high voltages must still be applied to the electrodes of themicrofluidic system. To eliminate the need for expensivepower supplies which are capable of generating continuous andprecise high voltages, the present invention provides forpower supplies which are time-multiplexed. These time-multiplexedpower supplies also reduce the number of powersupplies required for thesystem 100, since more than oneelectrode can be serviced by a time-multiplexed power supply.

Figure 3A illustrates the exemplary output of a highpower supply presently used in a electrokinetic system. Theoutput is constant at 250 volts between two electrodes overtime. In contrast, Figure 3B illustrates the output of apower supply operating according to the present invention. Tomaintain a constant voltage of 250 volts, the output voltageis time-multiplexed with a one-quarter duty cycle at 1000volts. Averaged in time, the output of the time-multiplexedvoltage supply is 250 volts, as illustrated by the horizontal dotted line across the graph. Note that if the voltage mustchange, say, in response to current control, as discussedabove, the output voltage of the time-multiplexed power supplycan also change by a change in the applied voltage, or by achange in the duty cycle, or a combination of both.

Electroosmotic fluid flow can be started and stoppedon the µsecond time scale in channels of the dimensionsdescribed here. Therefore, voltage modulation frequencieswhich are lower than one Megahertz result in choppy movementof the fluids. This should have no adverse effects on fluidmanipulation due to the plug flow nature of electroosmoticfluid. Because most chemical mixing, incubating andseparating events occur on the 0.1 to 100 second time scale,the much lower frequencies for voltage manipulation may beacceptable. As a rule of thumb, the modulation period shouldbe less than 1% of the shortest switching event (e.g.,switching flow from one channel to another) to keep mixing orpipetting errors below 1%. For a switching event of 0.1seconds, the voltage modulation frequency should be 1 KHz orhigher.

Figure 4A is a block diagram of a multiplexed powersupply system with twopower supplies 200 and 202 andcontroller block 204 for an exemplary and simple microfluidicsystem having achannel 180 which intersectschannels 182,184, 186 and 188. Thechannel 180 terminates inreservoirs179 and 181 withelectrodes 190 and 191 respectively. Thechannel 182 ends with areservoir 183 having anelectrode 193;thechannel 184 ends with areservoir 185 having anelectrode195; thechannel 186 with reservoir 187 having anelectrode197; and thechannel 188 withreservoir 189 having anelectrode 199.

The power supplies 200 and 202 are connected to thedifferent electrodes 190, 191, 193, 195, 197 and 199 of themicrofluidic system. Thepower supply 200 is connected tothreeelectrodes 190, 193 and 195, and thepower supply 202 isconnected to the remaining threeelectrodes 191, 197 and 199.Thecontroller block 204 is connected to each of the powersupplies 200 and 202 to coordinate their operations. For instance, to control the movements of fluids through thechannels 182, 184, 186 and 188, the voltages on theelectrodes190, 191, 193, 195, 197 and 199 must be properly timed. Thevoltages on the electrodes change in response to electriccurrent flow, as described above, for example, as thecontroller block 204 directs the power supplies 200 and 202.

Each of the power supplies 200 and 202 are organizedinto units illustrated in Figure 4B. Acontrol unit 212receives control signals from thecontrol block 204 anddirects the operation of aswitching unit 214. Theswitchingunit 214, connected to apower supply unit 216, makes orbreaks connections of thepower supply unit 216 to theconnected electrodes. In other words, theswitching unit 214time-multiplexes the power from thepower supply unit 216among its connected electrodes. Thepower supply unit 216 isalso connected to thecontrol unit 212 which directs thevariation of output from thepower supply unit 216 to theswitching unit 214. In an alternate arrangement, thisconnection to thecontrol unit 212 is not required if thepower supply unit 216 supplies a constant voltage and theaveraged voltage to a electrode is changed by varyingconnection duty cycle through theswitching unit 214.

Figure 6A is a block diagram of a power supply whichcould be used as thepower supply unit 216 in Figure 4B.Alternatively, the illustrated power supply may be connecteddirectly to an electrode of a microfluidic system if time-multiplexingis not used. The power supply can supply astable voltage to an electrode or to supply, or sink, a stablecurrent.

The power supply has aninput terminal 240 which issupplied with a controllable reference voltage from -5 to +5volts, which is stepped up in magnitude to hundreds of voltsat anoutput terminal 241. The input terminal is connected tothe negative input terminal of an inputoperational amplifier230 through anresistance 227. The positive input terminal ofanoperational amplifier 230 is grounded and its outputterminal is connected back to the negative input terminalthrough afeedback capacitor 220 andresistor 228 connected in series. The output terminal is also connected to an inputterminal of a DC-to-DC converter 231. A second input terminalis grounded. The output side of theconverter 231, whichsteps up the voltage received from theamplifier 230, isconnected to the powersupply output terminal 241. The secondoutput terminal of theconverter 231 is grounded through aresistor 222.

The powersupply output terminal 241 is alsoconnected to ground through two series-connectedresistances221 and 223 which form a voltage divider circuit. The nodebetween the tworesistances 221 and 223 is connected to oneinput terminal of a current/voltage mode switch 234. The nodeis also connected to the negative input terminal of a feedbackoperational amplifier 232 through aresistance 225. Thenegative input terminal is also connected to the outputterminal of theconverter 231 through aresistor 224 and tothe output terminal of theamplifier 232 through afeedbackresistor 226. The output terminal of theamplifier 232 isalso connected to a second input terminal of theswitch 234,which has its output terminal connected to the negative inputterminal of the inputoperational amplifier 230 through aresistor 226.

Theswitch 234 is responsive to a signal on thecontrol terminal 242. As shown in Figure 6A, theswitch 234connects its output terminal to either the output terminal ofthe feedbackoperational amplifier 232, or the voltage dividernode between the tworesistors 221 and 223. The connectiondetermines whether the power supply circuit operates in thevoltage mode (connection to the voltage divider node) or inthe current mode (connection to the output of the feedbackoperational amplifier 232). Note that theresistor 221 isvery large, approximately 15 MΩ, so that the voltage on theoutput terminal 241 can be easily fed back when the powersupply is operated.

The Figure 6A circuit may be separated intodifferent operational blocks. Theoperational amplifier 230,resistors 226-228 andcapacitor 220 are part of a mixingblock. The mixing block accepts the controllable reference voltage V_ref, about which the power supply operates, at theinput terminal 240 and a feedback voltage, discussed below, togenerate an output voltage, a combination of V_ref and feedbackvoltages, for the DC-DC converter 231. Theconverter 231,illustrated as a voltage amplifier in Figure 6B, simplyamplifies the voltage from theoperational amplifier 230. Oneoutput terminal of the voltage amplifier is connected to theoutput terminal 241 and a terminal of theresistor 221. Theother output of the voltage amplifier is connected to groundthrough theresistor 222. The resistors 221-223 may beconsidered as part of a feedback block which also hasresistors 224-226 andoperational amplifier 232. Theswitch234 is also part of the feedback block and is connected to thesecond input terminal of the mixing block, as describedpreviously.

Operationally, the mixing block has theoperationalamplifier 230 which is connected as a summing amplifier withthe resistances 226-228. With thecapacitor 220 in thefeedback loop of theoperational amplifier 230, the outputvoltage of theoperational amplifier 230 is the voltageintegrated over time of the sum (or difference) of thereference voltage V_ref and the feedback voltage from theswitch234. Of course, the reference voltage V_ref and feedbackvoltage may be selectively weighted by the values of theresistances 226 and 227. Thecapacitor 220 and theamplifier230 also act as a filter to remove high frequency fluctuationsfrom the power supply.

The output signal from theoperational amplifier 230may be conditioned, for example, rectified or buffered, byadditional elements (not shown). Nonetheless, for purposes ofunderstanding this invention, V_IN, the voltage received by theDC-DC converter 231, can be considered the same as the outputvoltage of theoperational amplifier 230. As shown in Figure6B, V_IN is amplified by a gain factor A and the amplifiedvoltage AV_IN is generated on theoutput terminal 241.

The feedback block has a voltage divider circuitformed by theresistors 221 and 223 connected between theoutput terminal 241 and ground. The voltage at the node between theresistors 221 and 223 is directly proportional tothe voltage at theoutput terminal 241. When theswitch 234in response to the signal on thecontrol terminal 242 selectsthe voltage feedback mode, the node voltage is fed directlyback to the mixing block and theoperational amplifier 230.The negative feedback stabilizes the output at the terminal241. For example, if the voltage at the terminal 241 is high,the feedback voltage is high. This, in turn, causes theoutput voltage of theoperational amplifier 230 to drop, thuscorrecting for the high voltage at theoutput terminal 241.For monitoring the voltage at theoutput terminal 241, thenode is also connected to anoperational amplifier 251,configured as a simple buffer, to send the feedback voltage toa monitoring circuit (not shown).

The feedback block also has theoperationalamplifier 232 and the resistances 224-226 which are connectedto configure theoperational amplifier 232 as a summingamplifier. One input to the summing amplifier is connected tothe node between theresistors 221 and 223. The second inputis connected to the node between theresistor 222 connected toground and the second output terminal of the DC-DC converter231. The summing amplifier measures the difference betweenthe amount of current through the series-connectedresistors221 and 223 and through the converter 231 (the total currentthrough theresistors 222 and 224). In effect, the summingamplifier measures the amount of current being deliveredthrough theoutput terminal 241. Thus when theswitch 234 isset in the current feedback mode, the output from theoperational amplifier 232 acting as a summing amplifier issent to the mixing block and the power supply circuit isstabilized about the amount of current being delivered throughthepower supply terminal 241 to a connected electrode of amicrofluidic system.

The output of the summing amplifier is alsoconnected to anoperational amplifier 250, configured as asimple buffer, to send the output voltage to the monitoringcircuit (not shown). From the outputs of theoperationalamplifiers 250 and 251, the monitoring circuit has a measure of the voltage at theoutput terminal 241 and of the currentthrough the terminal. This also allows the monitoring circuitto determine, and to regulate, the amount of power beingsupplied by the power supply circuit.

The ability of the described power supply to act asa variable source allows the direction of fluid flow throughthe microchannels of a microfluidic system to be changedelectronically. If all of the electrodes are connected to oneor more of the power supplies described above, operation ofthe microfluidic system is greatly enhanced and the desiredmovements of fluids through the network of channels in thesystem are much more flexible.

Despite operation as a current control system, thereis often still a need to determine the voltage at a node in amicrofluidic system. The present invention also provides ameans for such voltage monitoring. As shown in Figure 5A, anelectrical lead 160 is formed on the surface of asubstrate178 near a desirednode 173 in the microfluidic system. Thenode 173 is at the intersection ofchannel 170 havingreservoirs 169 and 171 at each end andchannels 172 and 174.The terminus of thechannel 174 has areservoir 175, while theterminus of the channel 172 (and a reservoir) is not shown.

Thelead 160 is preferably formed by the depositionof a conductive metal, or metal alloy, preferably a noblemetal, such as gold on chrome or platinum on titanium, used inintegrated circuits. With semiconductor photolithographytechniques, thelead 160 may be defined with widths of lessthan 1 µm. To prevent electrolysis, the width of thelead 160in thechannel 170 is narrow enough such that the voltageacross the lead in thechannel 170 should be less than 1 volt,preferably less 0.1 volt, at all times.

The voltages used in the microfluidic system arehigh. A voltmeter directly measuring the voltage at thechannel node 173 through thelead 160 must have a very highinput impedance to be capable of measuring such high voltages.Such voltmeters are expensive. Furthermore, handling of thesubstrate of the microfluidic systems increases thepossibility of contamination. Such contamination can seriously affect the voltages (and electric fields) requiredfor proper operation of electrokinetic forces in the channelsof the microfluidic system.

To avoid these problems and costs, thelead 160 isconnected to avoltage divider circuit 163, which is alsoformed on the surface of thesubstrate 178. The output of thevoltage divider circuit 163 is carried by aconductive outputlead 161. Thecircuit 163 is also connected by aconductivelead 162 to a voltage reference.

Thevoltage divider circuit 163, shown in greaterdetail in Figure 5B, is formed with standard semiconductormanufacturing technology withresistors 165 and 166 connectedas a voltage divider circuit. Thelead 160 is connected tothe input terminal of thecircuit 163, which is one end of alinear pattern of high-resistance material, such as undoped orlightly doped polysilicon or alumina. The other end of thelinear pattern is connected to thereference lead 162, whichis also formed on the substrate 168 and leads to an externalreference voltage, presumably ground. As shown forexplanatory purposes, the voltage of thelead 160 is dividedin a 10-to-1 ratio. The linear pattern is divided into aresistor 165 and aresistor 166. Theresistor 165 has ninetimes more loops than theresistor 166, i.e., the resistanceof theresistor 165 is nine times greater than the resistanceof theresistor 166. Of course, other ratios may be used anda 1000:1 ratio is typical. Theoutput lead 161, connectedbetween the tworesistors 165 and 166, leads to an externalconnection for a low-voltage reading by a voltmeter. Thecover plate then protects the leads 160-162, thevoltagedivider circuit 163 and the surface of the substrate fromcontamination.

While the foregoing invention has been described insome detail for purposes of clarity and understanding, it willbe clear to one skilled in the art from a reading of thisdisclosure that various changes in form and detail can be madewithout departing from the true scope of the invention. Allpublications and patent documents cited in this applicationare incorporated by reference in their entirety for all purposes to the same extent as if each individual publicationor patent document were so individually denoted.

Claims (51)

1. In a microfluidic system having a plurality ofinterconnected capillary channels and a plurality ofelectrodes at different nodes of said capillary channels forcreating electric fields in said capillary channels toelectrokinetically move materials in a fluid through saidcapillary channels, a method of operating said microfluidicsystem comprising
      applying voltages at said electrodes with respect toother electrodes in the system responsive to a current at saidelectrodes to move materials to and from channels of saidelectrodes.
2. The method of claim 1 wherein said microfluidicsystem has at least three electrodes.
3. The method of claim 2 wherein said voltageapplying step comprises controlling said voltage so that saidcurrent is substantially constant.
4. In a microfluidic system having a plurality ofcapillary channels and a plurality of electrodes at differentnodes of said capillary channels for creating electric fieldsin said capillary channels to electrokinetically movematerials in a fluid through said capillary channels, a methodof operating said microfluidic system comprising
      controlling in time an application of an electricalparameter between electrodes in the system to move materialstherebetween.
5. The method of claim 4 wherein said applicationis controlled such that said materials move equivalently to aconstant application of said electrical parameters betweensaid electrodes in the system.
6. The method of claim 5 wherein said applicationis controlled by varying a percentage of time said electricalparameter is applied.
7. The method of claim 4 wherein said electricalparameter comprises voltage.
8. The method of claim 4 wherein said electricalparameter comprises current.
9. The method of claim 4 wherein said electricalparameter comprises power.
10. A microfluidic system comprising

    a plurality of capillary channels in an insulatingsubstrate;

    a plurality of electrodes at different nodes of saidcapillary channels for creating electric fields in saidcapillary channels to electrokinetically flow materials in afluid through said capillary channels; and

    at least one conductive lead on said substrateextending to a capillary channel location so that a voltage atsaid capillary channel location may be determined.
11. The microfluidic system of claim 10 whereinsaid conductive lead has a sufficiently small width such thata voltage of less than 1 volt is created across saidconductive lead at said capillary channel location.
12. The microfluidic system of claim 11 whereinsaid conductive lead has a sufficiently small width such thata voltage of less than 0.1 volt is created across saidconductive lead at said capillary channel location.
13. The microfluidic system of claim 10 whereinsaid conductive lead is arranged to form a voltage dividercircuit on said substrate so that voltage received from said conductive lead is a fraction of said voltage at saidcapillary channel location.
14. The microfluidic system of claim 10 furthercomprising an insulating plate covering said substrate, saidconductive lead extending to an edge of said substrate.
15. A microfluidic system comprising

    a substrate having a plurality of interconnectedcapillary channels;

    a plurality of electrodes at different nodes of saidcapillary channels for creating electric fields in saidcapillary channels to move materials electrokinetically in afluid through said capillary channels;

    a power supply connected to at least one of saidelectrodes, said power supply further comprising

    a mixing block having a first input terminalfor receiving a controllable reference voltage and asecond input terminal, and an output terminal;

    a voltage amplifier connected to said mixingblock output terminal, said voltage amplifier havingfirst and second output terminals, said first outputterminal connected to said at least one electrode; and

    a feedback block connected to said first outputterminal of said voltage amplifier, said feedback blockhaving an output terminal connected to said second inputterminal of said mixing block so that negative feedbackis provided to stabilize said power supply.
16. The microfluidic system of claim 15 wherein saidfeedback block is connected to said first output terminalthrough a voltage divider circuit.
17. The microfluidic system of claim 16 whereinsaid feedback block provides feedback to said mixing blockresponsive to a voltage at said first output terminal.
18. The microfluidic system of claim 16 whereinsaid feedback block is connected to said second outputterminal of said voltage amplifier so that said feedback blockgenerates an output voltage responsive to an amount of currentbeing sourced or sunk through said first output terminal, saidfeedback block providing feedback to said mixing blockresponsive to said current amount being sourced or sunkthrough said first output terminal.
19. The microfluidic system of claim 18 whereinsaid feedback block has a summing amplifier having a firstinput connected to said voltage divider circuit and a secondinput connected to said second output terminal of said voltageamplifier, said summing amplifier generating said outputvoltage responsive to said current amount being sourced orsunk through said first output terminal.
20. The microfluidic system of claim 16 whereinsaid feedback block is connected to said second outputterminal of said voltage amplifier, said feedback blockgenerating a first feedback voltage responsive to a voltage atsaid first output terminal and a second feedback voltageresponsive to an amount of current being sourced or sunkthrough said first output terminal, said feedback block havinga switch for passing said first or second feedback voltage tosaid mixing block responsive to a control signal so that thepower supply is selectably stabilized by voltage or currentfeedback.
21. The microfluidic system of claim 20 furthercomprising first and second buffers connected to said feedbackblock, said first buffer transmitting said first feedbackvoltage and said second buffer transmitting said secondfeedback voltage so that said first and second feedbackvoltages may be monitored.
22. The microfluidic power supply of claim 15wherein said mixing block comprises an operational amplifierconnected as a summing amplifier.
23. The microfluidic power supply of claim 22wherein said operational amplifier is further connected as anintegrator.
24. A power supply for connection to at least oneelectrode of a microfluidic system comprising

    a mixing block having a first input terminal forreceiving a controllable reference voltage and a second inputterminal, and an output terminal;

    a voltage amplifier connected to said mixing blockoutput terminal, said voltage amplifier having first andsecond output terminals, said first output terminal connectedto said at least one electrode; and

    a feedback block connected to said first and secondoutput terminals of said voltage amplifier and to said secondinput terminal of said mixing block, said feedback blockgenerating a first feedback voltage responsive to a voltage atsaid first output terminal and a second feedback voltageresponsive to an amount of current being sourced or sunkthrough said first output terminal, said feedback block havinga switch for passing said first or second feedback voltage tosaid mixing block responsive to a control signal so that thepower supply is selectably stabilized in voltage or current bynegative feedback.
25. The power supply of claim 24 wherein saidfeedback block is connected to said first output terminal ofsaid voltage amplifier through a voltage divider circuit.
26. The power supply of claim 24 wherein saidfeedback block is connected to said second output terminal ofsaid voltage amplifier so that said feedback block generatesan output voltage responsive to an amount of current beingsourced or sunk through said first output terminal.
27. The power supply of claim 24 further comprisingfirst and second buffers connected to said feedback block,said first buffer transmitting said first feedback voltage andsaid second buffer transmitting said second feedback voltageso that said first and second feedback voltages may bemonitored.
28. The power supply of claim 26 wherein saidfeedback block has a summing amplifier having a first inputconnected to said voltage divider circuit and a second inputconnected to said second output terminal of said voltageamplifier, said summing amplifier generating said outputvoltage responsive to said current amount being sourced orsunk through said first output terminal.
29. The power supply of claim 24 wherein saidmixing block comprises an operational amplifier connected as asumming amplifier.
30. The power supply of claim 29 wherein saidoperational amplifier is further connected as an integrator.
31. A microfluidic system comprising

    a substrate having a plurality of interconnectedcapillary channels;

    a plurality of electrodes at different nodes of saidcapillary channels for creating electric fields in saidcapillary channels to move materials electrokinetically in afluid through said capillary channels;

    a plurality of power supplies connected to each oneof said electrodes, each of said power supplies capable ofselectively supplying a selected voltage or a selected amountof current as a source or sink to said connected electrodes.
32. The use of a substrate having at least onechannel in which a subject material is transportedelectrokinetically, by applying a voltage between two electrodes associated with said channel in response to acurrent at said electrodes.
33. A use of claim 32 in which the substrate has aplurality of interconnected channels and associatedelectrodes, subject material being transported alongpredetermined paths incorporating one or more of said channelsby the application of voltages to predetermined electrodes inresponse to a current at said electrodes.
34. The use of a substrate having at least onechannel in which a subject material is transportedelectrokinetically by the controlled time dependentapplication of an electrical parameter between electrodesassociated with said channel.
35. A use of claim 34 wherein said electricalparameter comprises voltage.
36. A use of claim 34 wherein said electricalparameter comprises current.
37. A use of claim 34 wherein said electricalparameter comprises power.
38. The use of an insulating substrate having aplurality of channels and a plurality of electrodes associatedwith said channels, the application of voltages to saidelectrodes causing electric fields in said channels, and atleast one conductive lead on said substrate extending to achannel location so that an electric parameter at said channellocation can be determined.
39. A use of claim 38 wherein said conductive leadhas a sufficiently small width such that a voltage of lessthan 1 volt, and preferably less than 0.1 volt, is createdacross said conductive lead at said channel location.
40. The use of an insulating substrate having aplurality of interconnected capillary channels, a plurality ofelectrodes at different nodes of said capillary channels forcreating electric fields in said capillary channels to movematerials electrokinetically in a fluid through said capillarychannels, a power supply connected to at least one of saidelectrodes, said power supply having a mixing block having afirst input terminal for receiving a reference voltage and asecond input terminal, and an output terminal; a voltageamplifier connected to said mixing block output terminal, saidvoltage amplifier having first and second output terminals,said first output terminal connected to said at least oneelectrode; and a feedback block connected to said first outputterminal of said voltage amplifier, said feedback block havingan output terminal connected to said second input terminal ofsaid mixing block so that negative feedback is provided tostabilize said power supply.
41. The use of claim 40 in which said feedbackblock is also connected to said second output terminal of saidvoltage amplifier, said feedback block generating a firstfeedback voltage responsive to a voltage at said first outputterminal and a second feedback voltage responsive to an amountof current being sourced or sunk through said first outputterminal, said feedback block having a switch for passing saidfirst or second feedback voltage to said mixing blockresponsive to a control signal so that said power supply isselectably stabilized by voltage or current feedback.
42. The use of a power supply for connection to atleast one electrode of a microfluidic system in which saidpower supply has a mixing block having a first input terminalfor receiving a reference voltage and a second input terminal,and an output terminal; a voltage amplifier connected to saidmixing block output terminal, said voltage amplifier havingfirst and second output terminals, said first output terminalconnected to said at least one electrode; and a feedback blockconnected to said first and second output terminals of said voltage amplifier and to said second input terminal of saidmixing block, said feedback block generating a first feedbackvoltage responsive to a voltage at said first output terminaland a second feedback voltage responsive to an amount ofcurrent being sourced or sunk through said first outputterminal, said feedback block having a switch for passing saidfirst or second feedback voltage to said mixing blockresponsive to a control signal so that said power supply isselectably stabilized in voltage or current by negativefeedback.
43. The use of a microfluidic system in which asubstrate has a plurality of interconnected capillarychannels, a plurality of electrodes at different nodes of saidcapillary channels for creating electric fields in saidcapillary channels to move materials electrokinetically in afluid through said capillary channels, and a plurality ofpower supplies connected to each one of said electrodes, eachof said power supplies capable of selectively supplying aselected voltage and a selected amount of current as a sourceor sink to said connected electrodes.
44. A microfluidic system comprising a substratehaving at least one channel in which a subject material istransported electrokinetically, means for measuring electricalcurrent and means for applying a voltage between twoelectrodes associated with said channel in response to saidcurrent at said electrodes.
45. A system as claimed in claim 44 in which thesubstrate has a plurality of interconnected channels andassociated electrodes, subject material being transportedalong predetermined paths incorporating one or more of saidchannels by the application of voltages to predeterminedelectrodes in response to a current at said electrodes.
46. A microfluidic system comprising a substratehaving at least one channel in which a subject material is transported electrokinetically, and means for the controlledtime dependent application of an electrical parameter betweenelectrodes associated with said channel.
47. A system as claimed in claim 46 wherein saidelectrical parameter comprises voltage.
48. A system as claimed in claim 46 wherein saidelectrical parameter comprises voltage.
49. A system as claimed in claim 46 wherein saidelectrical parameter comprises voltage.
50. A microfluidic system comprising an insulatingsubstrate having a plurality of channels and a plurality ofelectrodes associated with said channels, and means forapplying voltages to said electrodes in order to generateelectric fields in said channels, and at least one conductivelead on said substrate extending to a channel location so thatan electric parameter at said channel location can bedetermined.
51. A system as claimed in claim 50 wherein saidconductive lead has a sufficiently small width such that avoltage of less than 1 volt, and preferably less than 0.1volt, is created across said conductive lead at said channellocation.

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